Cognitive and language impairments are frequently observed in the elderly and in patients with Alzheimer's disease. The purpose of the proposed project is to clarify the nature and significance of these deficits, and to investigate their physiologic basis. Specifically, complex skills like picture naming and sentence comprehension will be decomposed into more fundamental, linguistically-and cognitively-motivated components using paper-and-pencil testing techniques which can be equally applied to mildly and severely demented patients. Deficits in performing these specific processes will be characterized in longitudinal and cross-sectional designs, allowing the development of rich profiles encompassing the full breadth of these complex cognitive skills. Positron emission tomography (PET) will be used to monitor cerebral perfusion at baseline and during cognitive activation with discrete intellectual tasks. Cognitive correlates of regional cerebral functioning will be defined, and a physiologically-based method for staging pDAT will be developed. Detailed histopathologic abnormalities in specific, language-related cerebral regions will be studied postmortem and related to end-stage language performance and in vivo PET. The results are hypothesized to show that complex language skills like naming and sentence comprehension can be decomposed into more fundamental linguistic components. Unique profiles of processing deficits for particular components will be seen in clusters of individuals, and we hypothesize that these are expected to change quantitatively as well as qualitatively during the natural history of Alzheimer's disease. Specific brain-behavior relations are hypothesized between regional PET defects evident on baseline scans and discrete cognitive difficulties in aging and dementia. Patterns of regional cerebral activity during PET activation studies will correlate with performance accuracy and lead to a physiologically-based in vivo staging algorithm for Alzheimer's disease. An end-stage deficit in performing specific linguistic skills is expected to be related to the topographic and cytoarchitectonic location and density of neurofibrillary tangles and senile plaques. These studies are expected to provide important guidelines for mapping discrete cognitive processes on to specific cerebral regions, to improve diagnostic and prognostic capabilities, to augment our knowledge of the biology of Alzheimer's disease and the normal aging process, and to help develop rational strategies for remediating well-defined language deficits in the dementias.